1. Field of the Invention
The invention generally relates to wound dressings and their methods of use. In particular, the invention provides wound dressings with associated active agents such as protease inhibitors and sequestrants which enhance the healing of wounds, especially chronic wounds.
2. Background of the Invention
The normal response to tissue injury is a timely and orderly reparative process that results in sustained restoration of anatomic and functional integrity. (Lazarus, et al. 1994). In contrast, in chronic ulcers, the healing process is prolonged, incomplete and proceeds in an uncoordinated manner resulting in poor anatomical and functional outcome. Clinically, wounds are categorized as acute and chronic based on the timeliness of healing.
Most chronic ulcers are associated with a small number of well-defined clinical entities particularly chronic venous stasis, diabetes mellitus, and pressure ulcers. These conditions are responsible collectively for approximately 70% of all chronic ulcers (Nwomeh et al. 1998). The incidence and prevalence of chronic ulcers vary considerably but are especially high in spinal cord injury patients as well as the elderly and nursing home population. As our society continues to age it is predicted that the incidence of chronic ulcers will continue to increase dramatically. Patients with pressure ulcers also have a significant socioeconomic impact on our society. For example, health care expenditures for treating pressure ulcers alone have been estimated to exceed $3 billion a year (Nwomeh, et al. 1998).
Normal healing involves a complex cascade of events involving interaction among many cell types, soluble factors and matrix components. Healing can be arbitrarily divided into overlapping temporal phases of coagulation, inflammation fibroplasia and finally remodeling. Most of the events are cytokine regulated. Normally, during the inflammatory phase, polymorphonuclear leukocytes(PMNs) are the first of the leukocytes to appear. They produce various proteases such as MMP-8 (collagenase) and elastase, which help to remove damaged matrix and aid in healing. In both the open acute and chronic wound, various cytokines are important in contraction and spontaneous closure of the wound as well as angiogenesis. Under normal circumstances, closure of the open wound is aided further by epithelization as these surface cells seal the final closure.
Chronic wounds are very different. For example, pressure ulcers are characterized by deep tissue necrosis with loss of muscle and fat that is disproportionately greater then the loss of overlying skin (Falanga, et al. 1998). These defects are common among the immobilized and debilitated. There are approximately 225,000 spinal cord injury patients in the United States and approximately 9,000 new cases per year. Approximately 60% of these patients develop pressure ulcers and the annual cost is greater then $25,000 per patient for medically related care. (Allman, 1998) If the elderly nursing home population with pressure ulcers in added to the spinal cord injury population then the figure for the care of all pressure ulcers is enormous.
To date, the majority of the effort to improve rates of healing of chronic wounds have focused on the use of exogenous peptide growth factors and cell based products such as cytokines. For the most part, these attempts have met with little notable success. Another alternative approach has been the use of xe2x80x9cskin substitutesxe2x80x9d such as Apligraf (matrix+cells) and Dermagraft (matrix+cells). While this second approach has shown some promise, its expense presently greatly limits its use to the richer developed countries. Various modifications of the wound dressings have also been suggested as a means to augment would healing.
Further examples include:
U.S. Pat. No. 5,098,417 to Yamazaki et al. teaches the ionic bonding of physiologically active agents to cellulosic wound dressings.
U.S. Pat. No. 4,453,939 to Zimmerman et al. teaches the inclusion of aprotonin in composition for xe2x80x9csealing and healingxe2x80x9d of wounds.
U.S. Pat. No. 5,807,555 to Bonte et al. teaches the inclusion of inhibition for alpha-1-protease, collagenase, and elastase in pharmaceutical compositions for promotion of collagen synthesis.
U.S. Pat. No. 5,696,101 to. Wu et al., teaches use of oxidized cellulose (e.g. Oxycel) as a bactericide and hemostat in treatment of wounds.
World Patent WO 98/00180 to Watt et al. teaches complexation of oxidized cellulose with structural proteins (e.g. collagen) for chronic wound healing; and references the utility of oligosaccharide fragments produced by the breakdown of oxidized cellulose in vivo in the promotion of wound healing.
Neutrophils are a predominant infiltrating inflammatory cell type present in the acute inflammatory response. Neutrophils function primarily to destroy invading pathogens and to debride devitalized tissue at the site of injury. The normal adult produces approximately 1011 neutrophils per day. To function effectively in host defense, they must migrate to the site of inflammation and release selectively a large repertoire of lytic enzymes, antimicrobial peptides, and potent oxidants from cytoplasmic granules. Under other conditions, the neutrophil has been implicated in causing disease by damaging normal host tissue. Such inflammatory tissue injury are important in the pathogenesis of a variety of clinical disorders including arthritis, ischemia-reperfusion tissue injury and systemic inflammatory response syndrome (SIRS) and the acute respiratory distress syndrome (ARDS). (Weiss, 1989) There is strong evidence that neutrophils also may have a significant role in the pathophysiology of pressure ulcers.
Neutrophils are a prevalent cell type in pressure ulcers. (Diegelmann, et al. 1999; Paloahti, et al. 1993; Rogers et al. 1995) In addition, there is direct evidence correlating neutrophil products with chronic pressure ulcers. (Yager, et al. 1996; Yager, et al. 1997). This includes neutrophil elastase, gelatinase (MMP-9) as well as collagenase (MMP-8). (Wysocki, 1996; Wysocki et al, 1993; Yager et al. 1997; Yager et al. 1996). Therefore, these observations and the evidence that neutrophils have been implicated in tissue destruction in other inflammatory processes give strong credence to the hypothesis that neutrophil products are involved in the pathogenesis of pressure sores and subsequent failure to heal. Neutrophil-derived MMP-8 has been shown to be the predominant collagenase in both acute and chronic wounds. (Nwomeh, et al. 1999).
Neutrophils contain large amounts of elastase (1 pg/cell). This serine protease has a broad substrate spectrum. As with neutrophil-derived MM-8, elastase levels have also been found to be significantly elevated in fluid derived from pressure ulcers. (Yager et al. 1997) The presence of high levels of active elastase with a wound site may have important implications for wound healing therapies utilizing peptide growth factors. Elastase present in chronic wounds can degrade peptide growth factors such as PDGF and TGF-b. (Yager et al. 1997). Moreover, cell surface receptors for peptide growth factors may themselves be functionally inactivated by the actions of elastase. Elastase may also contribute to the overall proteolytic environment of chronic wounds. It is known to proteolytically inactivate the specific inhibitor, Tissue Inhibitor of Metalloproteinases (TIMP). In addition, elastase itself may participate in proteolytically activating collagenase and gelatinase zymogens. Obviously, an unregulated proteolytic environment can be a significant aspect of the pathophysiology of chronic wounds.
It would be highly beneficial to have available additional methods for enhancing wound healing. In particular, methods directed to bringing the proteolytic environment of wounds under control in order to promote wound repair would be desirable. Such methods would be useful in the treatment of wounds in general, and chronic wounds in particular. Further, it would be highly beneficial if such methods were inexpensive and thus widely accessible.
It is an object of this invention to provide novel wound dressings for the treatment of wounds, especially for the treatment of chronic, non-healing wounds. The wound dressings of the instant invention are comprised of a support matrix and an active agent associated with the support matrix. In preferred embodiments of the invention, the support matrix is cellulose or carboxymethylated cellulose.
The active agents may be protease inhibitors. Protease inhibitors especially suited to the practice of the instant invention include those which inhibit neutrophil-derived proteases, an overabundance of which are found in chronic wounds. In particular, these are cationic proteases, such as elastase. Examples of such inhibitors include peptide inhibitors such as di- or tri-peptide sequence such as Val-Pro, Pro-Val, Ala-Pro-Val or Val-Pro-Ala; or tetrapeptide sequences containing Ala-Pro-Val or Val-Pro. These inhibitors may be associated with the support matrix via covalent, non-covalent or ionic linkages. Further, the inhibitors may be dissociable from the matrix. Upon exposure to the wound fluid, the inhibitors may be released from the matrix and migrate into the wound microenvironment.
The active agents may also be sequestrants. Substances suitable as sequestrants may also be protease inhibitors (as listed above). Alternatively, sequestrants may be of a more general nature, for example, sulfonyl, phosphate, or aldehyde groups associated with the support matrix. The sequestrants bind proteases found in the wound fluid and remove them from the wound microenvironment.
The invention also provides methods of use for the wound dressings, including a method for sequestering elastase at a wound site. This method comprises the step of contacting the wound site with a wound dressing selected form the group consisting of carboxymethylcellulose, dialdehyde gauze, sulfonated gauze, and phosphorylated gauze.
The dressings may be applied to wounds in order to enhance would healing, especially the healing of chronic wounds.